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Abstract
Mutations in the SERPINA1 gene can cause deficiency in the circulating serine protease inhibitor α1-Antitrypsin (α1AT). α1AT deficiency is the major contributor to pulmonary emphysema and liver disease in persons of European ancestry, with a prevalence of 1 in 2500 in the USA. We present the discovery and characterization of a novel SERPINA1 mutant from an asymptomatic Middle Eastern male with circulating α1AT deficiency. This 49 base pair deletion mutation (T379Δ), originally mistyped by IEF, causes a frame-shift replacement of the last sixteen α1AT residues and adds an extra twenty-four residues. Functional analysis showed that the mutant protein is not secreted and prone to intracellular aggregation.
Highlights
Mutations in the SERPINA1 (PI) gene can cause loss or deficiency in the circulating serine protease inhibitor, a1-Antitrypsin (a1AT). a1AT is primarily secreted by the liver and plays a key role in protecting the lower respiratory tract from proteolytic damage by inhibiting neutrophil elastase
Over 100 SERPINA1 mutations have been identified to date, at least 30 of which have been implicated in disease pathogenesis [5]. a1AT deficiency is best managed with early and accurate diagnosis, which presents challenges because of the polymorphic nature of this gene as well as limitations associated with isoelectric focusing (IEF) testing
In this study we describe a novel 49 base pair deletion of the SERPINA1 gene in a patient presenting with deficiency of circulating a1AT
Summary
Mutations in the SERPINA1 (PI) gene can cause loss or deficiency in the circulating serine protease inhibitor, a1-Antitrypsin (a1AT). a1AT is primarily secreted by the liver and plays a key role in protecting the lower respiratory tract from proteolytic damage by inhibiting neutrophil elastase. Mutations in the SERPINA1 (PI) gene can cause loss or deficiency in the circulating serine protease inhibitor, a1-Antitrypsin (a1AT). Normal a1AT levels, resulting from two copies of the common SERPINA1 M allele, range between 1.5 and 3.5 g/l. Clinical conditions associated with a1AT deficiency primarily arise from either tissue damage due to uncontrolled elastase activity in the lungs, or from accumulation of misfolded or aggregated protein in the liver [3]. SERPINA1 alleles are expressed codominantly, the type and combination of mutations will result in varying levels of circulating a1AT and associated clinical manifestation. In this study we describe a novel 49 base pair deletion of the SERPINA1 gene in a patient presenting with deficiency of circulating a1AT
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